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SCIENCE AT THE EDGE SEMINAR QB/GEDD Friday, December 10 at 11:30am Room 1400 Biomedical and Physical Sciences Bldg. Refreshments at 11:15 Daniel Weinrich Department of Ecology and Evolutionary Biology, and Center for Computational Molecular Biology, Brown University Dissecting the Mechanistic Determinants of Adaptation The phenotypic consequence of a mutation often depends on what other mutations are present in the genome, a phenomenon called epistasis. We first show formally that such epistatic interactions can constrain adaptation, since an important mutation may not be beneficial in the current genetic background, and further that epistasis substantially constrains the evolution of beta-lactamase, a key antibiotic resistance enzyme in E. coli. This raises the question of mechanism: why does the same mutation increase drug resistance in some allelic backgrounds while reducing it in others? Mutational tradeoffs between enzyme stability and kinetics are at least partly responsible, and this appears to be a rather general property of protein evolution, implying that epistatic constraints on adaptation will be widespread. Such mutational tradeoffs are the essence of RA Fisher's Geometric model of evolution through phenotype space, and we show how his quantitative framework can be used to make inferences about the shape and size of phenotype space in any system using only data on epistasis. Time permitting we will conclude with an overview of a new project seeking to dissect the mechanistic determinants of adaptation in the bacteriophage phiX-174. Helen Geiger Administrative Assistant Quantitative Biology Graduate Program/ Gene Expression in Development & Disease Michigan State University 502B Biochemistry Building East Lansing, MI 48824 Phone: (517) 432-9895 Fax: (517) 353-9334 E-mail: [log in to unmask]<mailto:[log in to unmask]> Web: http://qbmi.msu.edu<http://qbmi.msu.edu/> http://www.bch.msu.edu/GEDD/index.htm<http://www.bch.msu.edu/GEDD/MSU-TRSB-Symposium.htm>